Chemistry

Carboxylic acid derivatives

Session - 3

Session objectives

1. Nomenclature

2. Structures of the functional groups

3. Physical properties

4. Preparation of acyl halides and reactions

5. Preparation of acid anhydrides and reactions

6. Preparation of esters and their reactions

7. Preparation of amides and their reactions

Introduction

Acyl group bonded to Y, an electronegative atom or leaving group

Includes: Y = halide (acid halides), acyloxy (anhydrides), alkoxy (esters), amine (amides), thiolate (thioesters), phosphate (acyl phosphates)

Naming Carboxylic Acid Derivatives

Acid Halides, RCOX

Derived from the carboxylic acid name by replacing the -ic acid ending with -yl or the -carboxylic acid ending with –carbonyl and specifying the halide

Naming Acid Anhydrides, RCO2COR‘

If symmetrical replace “acid” with “anhydride” based on the related carboxylic acid (for symmetrical anhydrides)

From substituted monocarboxylic acids: use bis- ahead of the acid name

Unsymmetrical anhydrides— cite the two acids alphabetically

Naming Amides, RCONH2

With unsubstituted NH2 group. replace -oic acid or -ic acid with -amide, or by replacing the -carboxylic acid ending with –carboxamide

If the N is further substituted, identify the substituent groups (preceded by “N”) and then the parent amide

Naming Esters, RCO2R

Name R’ and then, after a space, the carboxylic acid (RCOOH), with the “-ic acid” ending replaced by “-ate”

Summary of nomenclature

Relative Reactivity of Carboxylic Acid Derivatives

More electrophilic carbonyl groups are more reactive to addition (acyl halides are most reactive, amides are least)

The intermediate with the best leaving group decomposes fastest

Nucleophiles react more readily with unhindered carbonyl groups

Substitution in Synthesis

We can readily convert a more reactive acid derivative into a less reactive one

Reactions in the opposite sense are possible but require more complex approaches

Nucleophilic Acyl Substitution

Carboxylic acid derivatives have an acyl carbon bonded to a group Y that can leave

A tetrahedral intermediate is formed and the leaving group is expelled to generate a new carbonyl compound, leading to substitution

General Reactions of Carboxylic Acid DerivativesWith water carboxylic acid

With alcohols esters

With ammonia or an amine an amide

With hydride source an aldehyde or an alcohol

With Grignard reagent a ketone or an alcohol

Boiling Points

Even 3 amides have strong attractions.

Melting Points

H C

O

NCH3

CH3CH3 C

O

NH

CH3

CH3CH2 C

O

N

H

H

m.p. -61C m.p. 28C m.p. 79C

Amides have very high melting points.

Melting points increase with increasing number of N-H bonds.

Solubility

Acid chlorides and anhydrides are too reactive to be used with water or alcohol.

Esters, 3 amides, and nitriles are good polar aprotic solvents.

Solvents commonly used in organic reactions:

– Ethyl acetate

– Dimethylformamide (DMF)

– Acetonitrile

Preparation of acid derivatives

Must enhance reactivity

Convert OH into a better leaving group

Specific reagents can produce acid chlorides, anhydrides, esters, amides

From carboxylic acids into acid ChloridesReaction with thionyl chloride, SOCl2.

Reaction with PBr3.

Reactions of Acid Halides

Nucleophilic acyl substitution

Halogen replaced by OH, by OR, or by NH2

Reduction yields a primary alcohol

Grignard reagent yields a tertiary alcohol

Hydrolysis: Conversion of Acid Halides into Acids

Acid chlorides react with water to yield carboxylic acids

HCl is generated during the hydrolysis: a base is added to remove the HCl

Conversion of Acid Halides to Esters

Esters are produced in the reaction of acid chlorides react with alcohols in the presence of pyridine or NaOH

The reaction is better with less steric bulk

Aminolysis: Conversion of Acid Halides into Amides

Amides result from the reaction of acid chlorides with NH3, primary (RNH2) and secondary amines (R2NH)

The reaction with tertiary amines (R3N) gives an unstable species that cannot be isolated

HCl is neutralized by the amine or an added base

Reduction: Conversion of Acid Chlorides into AlcoholsLiAlH4 reduces acid chlorides to yield aldehydes and then primary alcohols

Reaction of Acid Chlorides with Organometallic ReagentsGrignard reagents react with acid chlorides to yield tertiary alcohols in which two of the substituents are the same

Formation of Ketones from Acid Chlorides

Reaction of an acid chloride with a lithium diorganocopper (Gilman) reagent, Li+ R2Cu

Addition produces an acyl diorganocopper intermediate, followed by loss of RCu and formation of the ketone

Preparation of acid anhydrides

Heat cyclic dicarboxylic acids that can form five- or six-membered rings

from acid chlorides and carboxylic acids

Reactions of Acid Anhydrides

Similar to acid chlorides in reactivity

Acetylation

Acetic anhydride forms acetate esters from alcohols and N-substituted acetamides from amines

Chemistry of Esters

Many esters are pleasant-smelling liquids: fragrant odors of fruits and flowers

Also present in fats and vegetable oils

Preparation of Esters

Esters are usually prepared from carboxylic acids

Preparation of esters

Methods include reaction of a carboxylate anion with a primary alkyl halide

Fischer Esterification

Heating a carboxylic acid in an alcohol solvent containing a small amount of strong acid produces an ester from the alcohol and acid

Fischer Esterification: Detailed Mechanism

1

2

3

4

1. Protonation of carbonyl oxygen activates the carboxylic acid.

2. Towards nucleophilic attack by alcohol, yielding a tetrahedral intermediate.

3. Transfer a proton from one oxygen atom to another yields a second tetrahedral intermediate and converts the —OH group into a good leaving group.

5. Loss of a proton and expulsion of a H2O regenerates the acid catalyst and gives the ester product.

Reactions of Esters

Less reactive toward nucleophiles than are acid chlorides or anhydrides

Cyclic esters are called lactones and react similarly to acyclic esters

Hydrolysis: Conversion of Esters into Carboxylic Acids

An ester is hydrolyzed by aqueous base or aqueous acid to yield a carboxylic acid plus an alcohol

Acid Catalyzed Ester Hydrolysis

The usual pathway is the reverse of the Fischer esterification

Aminolysis of Esters

Ammonia reacts with esters to form amides

Reduction: Conversion of Esters into Alcohols

Reaction with LiAlH4 yields primary alcohols

Partial Reduction to Aldehydes

Use one equivalent of diisobutylaluminum hydride (DIBAH = ((CH3)2CHCH2)2AlH)) instead of LiAlH4

Low temperature to avoid further reduction to the alcohol

Reaction of Esters with Grignard Reagents

React with 2 equivalents of a Grignard reagent to yield a tertiary alcohol

Chemistry of Amides

Prepared by reaction of an acid chloride with ammonia, monosubstituted amines, or disubstituted amines

Reactions of Amides

Heating in either aqueous acid or aqueous base produces a carboxylic acid and amine.

Acidic hydrolysis by nucleophilic addition of water to the protonated amide, followed by loss of ammonia.

Basic hydrolysis of amides

Addition of hydroxide and loss of amide ion

Reduction: Conversion of Amides into Amines

Reduced by LiAlH4 to an amine rather than an alcohol

Converts C=O CH2

Mechanism of Reduction

Addition of hydride to carbonyl group

Loss of the oxygen as an aluminate anion to give an iminium ion intermediate which is reduced to the amine

Thank you